Investigation of Mechanism of Action of Selected Drugs Against Experimentally Induced Alzheimer's Disease Model in Rats

Abstract

Background and objectives: Alzheimer’s disease is most common form of dementia which is age related disorder. In U.S, 5.82 million people of all age are living with dementia in year of 2019. In that 5.6 million of age of 65 and older and 2,00,000 people of younger age having dementia. Currently there is not any disease modifying therapy available for the treatment of Alzheimer’s disease. Current therapy includes the cholinesterase inhibitors and memantine which is NMDA antagonist. These classes of drugs do not cure the disease but improve memory by increasing the level of Acetylcholine and decrease the excessive toxic effect of glutamate. There are many disease conditions which affect the brain physiology i.e., diabetes mellitus, viral infection. So that there is need to find the new strategies for the complete treatment of Alzheimer’s disease. The main objective of this study is to find the new targets for the treatment. We choose the two drugs for repurposing for irradiation of AD and those are Canagliflozin and valacyclovir. Canagliflozin is SGLT2 inhibitor which is mainly used to treat type-2 diabetes mellitus. Epidemiological statistics shows that patient having T2DM has more chances to develop Alzheimer’s disease. From the post-mortem analysis of brain of Alzheimer’s patient researchers found the presence of HSV virus in the brain of the patient. So, it is important to check the connection between viral infection and AD. We choose valacyclovir which is DNA polymerase inhibitor. Previous in-silico study suggests that valacyclovir bind with the NMDA, acetylcholine esterase, butyrylcholine esterase and beta-site amyloid precursor protein cleaving enzyme 1(BACE1) enzyme and block their activity. So, in-vivo correlation is needed to be investigated. The main objectives of the study were to investigate the pharmacological effect and mechanism of action of valacyclovir and Canagliflozin for the treatment of Alzheimer’s disease.Material and methods: To generate Alzheimer’s disease like condition we chose two different model. In first model Alzheimer’s disease was induced by aluminium chloride and in second model Alzheimer’s disease was induced by injecting streptozotocin through intracerebroventricular route. After the disease induction disease control groups (AlCl3 model) were treated with donepezil (5mg/kg), valacyclovir (100 mg/kg), valacyclovir (150 mg/kg) and in streptozotocin treated model donepezil (5 mg/kg). as standard treatment and two doses of Canagliflozin (9 mg/kg and 18 mg/kg). To evaluate the dementia, neurobehavioral tests Y-maze and Morris water maze were performed prior to induction of AD and after the treatment of valacyclovir and Canagliflozin. After completion of neurobehavioral parameters animals were sacrificed and brain was removed and subjected for analysis of biochemical parameters like oxidative stress parameters, anti-inflammatory parameters and histopathology of brain tissue was done. Results: Streptozotocin induced Alzheimer’s model: In Y-maze test, Canagliflozin treatment increased the percentage time spent in novel arm as compared to disease control group but improvement was lower than in standard treated group. In water-maze test, the Canagliflozin treated group showed improvement in disease condition but dose dependency was not seen. The results of antioxidant and anti-inflammatory parameters were not significant. Histology of Canagliflozin treated animal showed that the treatment with Canagliflozin prevented the pyramidal cell loss as observed in disease control group.